Bioactive cytochalasans from the desert soil-derived fungus 375 obtained via a chemical engineering strategy.

The chemical engineering of natural extracts has emerged as an effective strategy for the production of diverse libraries of chemicals, making it integral to drug discovery. A chemical engineering strategy based on the epoxidation and ring-opening reactions was used to prepare diversity-enhanced extracts of 375. Eleven unnatural cytochalasan derivatives () with unique functional groups, such as amine and isoxazole, were isolated and characterized from these chemically engineered extracts of 375. The identification of these new structures was accomplished through comprehensive spectroscopic analysis, supplemented by synthetic considerations. Notably, compounds and - displayed potent phytotoxic effects on , while compounds , , , , and demonstrated inhibitory activities on LPS-induced NO production in RAW264.7 cells. Among them, compound was found to be able to inhibit the upregulated expression of the inducible nitric oxide synthase (iNOS) protein induced by LPS, while also decreasing the production of pro-inflammatory cytokines (IL-6) and influencing the phosphorylation of p38, ERK1/2, and JNK at 100 μM. Our findings demonstrate that the chemical engineering of natural product extracts can be an efficient technique for the generation of novel bioactive molecules.